Glucose-6-phosphate dehydrogenase (G6PD) is a potent antioxidant enzyme. G6PD deficiency, predominant among males, is a neonatal "neurotoxic" risk, characterized by episodic hemolysis that is sometimes infection triggered. Clinical risk among heterozygous G6PD-deficient females is often under-recognized. Recent reports of rhabdomyolysis among G6PD-deficient individuals are reviewed here. In one case, a male athlete with G6PD deficiency (<10% activity) experienced multiple, acute episodes of rhabdomyolysis, painful muscle symptomatology, injury and hemolysis after strenuous exertion. Both his mother with G6PD-deficiency (<45% activity) and maternal grandmother have chronic histories of episodic or triggered fatigue-related disruptive symptoms. Other case reports of G6PD-deficient individuals with muscle injury and exertional symptoms (with or without hemolysis) showed unique laboratory findings of elevated creatine kinase, myoglobin, lactate dehydrogenase, creatinine, and aminotransferases levels and myoglobinuria. Disrupted myocyte energetics and loss of cellular integrity can be attributed to impaired downstream pentose phosphate pathway (PPP)-related oxidant stress protection, which is a key enzymatic consequence of G6PD-deficiency. These triggered stresses may explain the muscle fatigue and propensity to exertional injury. Correlation between stress-sensitive-impaired muscle injury among all G6PD-deficient individuals, including neonates, requires further clinical validation to ascertain oxidant-stress impact of impaired PPP-dependent cellular energetics of red blood, white blood, neural, and muscle cells.

Macrophages regulate inflammatory responses in hyperlipidemia and dysmetabolic states while performing a critical homeostatic function by clearing damaged or senescent red blood cells (RBCs) through erythrophagocytosis. This process delivers heme and iron that must be detoxified and recycled through NADPH-dependent pathways. Glucose-6-phosphate dehydrogenase deficiency (G6PDd), affecting ~6% of the global population, limits NADPH generation and predisposes RBCs to oxidative damage and hemolysis. Whether G6PD deficiency alters macrophage metabolic responses to RBC clearance in hyperlipidemic environments remains unknown. Humanized mouse models expressing canonical (hG6PDND), African (hG6PDA-), or Mediterranean (hG6PDMed-) G6PD variants were exposed to Western diet-induced hyperlipidemia. RBCs, plasma, and splenic macrophages were analyzed using metabolomics, lipidomics/oxylipin profiling, and quantitative proteomics. Hyperlipidemia increased circulating lipid species and altered RBC metabolism, while G6PD deficiency selectively reduced pentose phosphate pathway intermediates. Plasma metabolomics revealed signatures consistent with increased hemolysis in hyperlipidemic G6PD-deficient mice. Splenic macrophages from G6PDd animals showed biochemical evidence of erythrophagocytosis, glutathione depletion, and remodeling of central carbon metabolism. Variant-specific alterations included increased glycolytic flux, disrupted TCA cycle activity, and elevated succinate/fumarate ratios consistent with mitochondrial dysfunction. Proteomics revealed extensive mitochondrial and proteasomal remodeling. G6PD deficiency and hyperlipidemia converge to reprogram macrophage metabolism through NADPH limitation, redox imbalance, and impaired handling of RBC-derived metabolites. These findings identify an NADPH-dependent metabolic vulnerability linking RBC fragility, erythrophagocytosis, and inflammatory macrophage reprogramming.

Glucose-6-phosphate dehydrogenase (G6PD), the committed enzyme of the pentose phosphate pathway, plays a pivotal role in glucose metabolism, which is integral to platelet biology. Although G6PD deficiency is a prevalent enzyme defect worldwide, the specific role of G6PD itself in platelets remains unclear. Herein, we discover a previously unrecognized phenotype in both human patients and murine models, demonstrating that G6PD deficiency leads to elevated platelet counts through enhanced proplatelet formation (PPF). Mechanistically, we reveal a non-canonical function of G6PD in regulating actin dynamics via its interaction with an actin-binding protein, tropomodulin-3 (TMOD3). The G6PD-TMOD3 interaction, which is concentration-dependently enhanced by nicotinamide adenine dinucleotide phosphate (NADP[+]), can limit actin rearrangement, thereby inhibiting PPF. Furthermore, we develop a G6PD-derived peptide, GC2P2, which potentiates the G6PD-TMOD3 interaction and significantly suppresses thrombocytopoiesis both in vitro and in vivo. In conclusion, our findings suggest that G6PD deficiency facilitates platelet biogenesis by altering TMOD3-mediated actin dynamics. The study provides new insights into thrombopoiesis and offers potential strategies for modulating platelet production.

India has a high burden of Plasmodium vivax malaria. Current malaria treatment guidelines recommend a total primaquine dose of 3·5 mg/kg administered over 14 days to prevent relapse in P. vivax infection, however, adherence is generally poor, impacting effectiveness. We aimed to determine the efficacy and safety of the same total dose of 3·5 mg/kg administered over 7 days in India.

An adult male patient in his late teens presented with pruritus, nausea and progressive jaundice after travel to West Africa. He did not get a pre-travel hepatitis A vaccination or malaria chemoprophylaxis. Laboratory testing demonstrated hepatocellular injury with alanine aminotransferase (ALT) 4002 U/L (reference <60), marked hyperbilirubinaemia (total bilirubin 632 µmol/L, reference <20) and a mildly prolonged international normalised ratio (INR). Concurrently, he developed non-immune haemolysis with undetectable haptoglobin, elevated lactate dehydrogenase and reticulocytosis, as well as bite and blister cells on blood film with a negative direct antiglobulin test. Acute hepatitis A virus infection was confirmed and enzymatic testing showed glucose-6-phosphate dehydrogenase deficiency. Haemoglobin electrophoresis also identified sickle cell trait. He improved with supportive care, avoidance of oxidant medications and close monitoring without renal injury or need for transfusion. This case illustrates an approach to jaundice in a returning traveller, the recognition of oxidative haemolysis at the bedside and preventive opportunities.

Infants with glucose-6-phosphate dehydrogenase (G6PD) deficiency are at increased risk for extreme hyperbilirubinemia. However, distinguishing these at-risk infants from the general population can be a diagnostic challenge for the managing pediatrician. Most instances of hyperbilirubinemia follow a benign course, which can give pediatricians a false sense of complacency regarding the likelihood of an infant having a devastating outcome. This case highlights how easily a tragedy such as kernicterus can occur, and addresses how careful application of the 2022 American Academy of Pediatrics Clinical Practice Guideline Revision can aid in the identification of infants at risk and optimization of management of infants with unknown G6PD status.

The malaria hypothesis proposes that in areas with a high incidence of malaria transmission, there is likely to be a high prevalence of genetic variants that confer protection against the disease. These resistance variants, located at different loci, may be statistically associated, leading to a non-random alteration in allele frequencies and exhibiting fitness levels that are not independent across loci (epistatic interaction). The aim of this study was to investigate whether signatures of epistatic selection exist between the Duffy and G6PD loci and to estimate the adaptive values associated with their genotype combinations in the population of Buenaventura, a malaria-endemic region of the Colombian Pacific. To achieve this, the indices DST[2], DIS[2], D'IS[2], and D'ST[2] were calculated to partition the variance of linkage disequilibrium (LD) between pairs of loci, using the OhtaDstats package in R software. Additionally, fitness values and selection coefficients were estimated for the genotypic combinations of these variants. To our knowledge, this study provides the first evidence of epistatic selection between the Duffy and G6PD loci in a malaria-endemic population from the Colombian Pacific, an interaction not previously reported in the literature using a linkage disequilibrium-based approach. This finding is supported by the calculated indices, as well as by the higher fitness values observed in genotype combinations involving these resistance variants. The observed interaction may reflect complementary protection against different Plasmodium species and the absence of physiological antagonism between the two resistance mechanisms.

This article chronicles the life of James Earl Bostic, known affectionately to his family and friends as "King James." We provide a parental and family perspective on the incredibly challenging journey he faced with his family resulting from unnecessary suffering due to kernicterus, a completely preventable disease. As his mother, I struggled to understand the significant impact of hyperbilirubinemia triggered by glucose-6-phosphate dehydrogenase (G6PD) deficiency, while also raising his sibling and navigating broken systems of care. I became a tireless advocate, pushing his educational team to assume capability and ensure he had access to robust language and literacy skills. I also repeatedly advocated for deep brain stimulation (DBS) to manage his tone, which was only granted after going before an Independent Review Board while he experienced prolonged, life-threatening dystonic crisis. My advocacy proved highly effective. DBS gave him upward and downward eye movement that enabled him to successfully access an eye gaze activated communication device, finally gaining expressive communication. He leveraged that device to validate what those who loved him knew - he had language, emotions, and a very sarcastic sense of humor! King James later addressed medical professionals during the 2019 Kernicterus Symposium at the Pediatric Academic Societies (PAS), describing how hard it was for him without communication and urging everyone to provide a meaningful education to children with special health needs. His story shows the catastrophic impact of bilirubin neurotoxicity while also emphasizing the critical importance of nurturing the whole child, assuming capability, providing equitable access to a high-quality education, and honoring self-direction.

Background: G6PD deficiency is among the leading causes of neonatal hyperbilirubinemia and kernicterus. Following a 2022 New York State Department of Health recommendation to test high-risk neonates, we implemented universal G6PD deficiency screening in the well-baby nursery. Objectives: We aimed to increase the proportion of infants screened from 0% to more than 75% within 6 months and to describe the prevalence of G6PD deficiency and the early outcomes of affected neonates. Methods: This quality improvement (QI) initiative, guided by the Model for Improvement, included a cross-sectional analysis of screening yield and early neonatal outcomes. A statistical process control p-chart tracked monthly screening. Outcomes were compared between screen-positive and screen-negative infants using the Fisher exact test. Results: Screening rose from 0% to a sustained mean of 81.1%, exceeding the 75% aim. Of 580 screened neonates, 52 (9.0%) screened positive for G6PD deficiency. Screen-positive infants were more likely than screen-negative infants to undergo repeat serum bilirubin testing (38.5% vs. 19.3%; p = 0.002) and to reach a peak bilirubin above 10 mg/dL (30.8% vs. 10.2%; p < 0.001). A higher rate of readmission for phototherapy was also observed (5.8% vs. 0.9%; p = 0.028), though based on few events. Phototherapy during the birth hospitalization, IVIG, and exchange transfusion did not differ. Conclusions: Universal G6PD screening was feasibly implemented and sustained in a high-risk well-baby nursery through routine workflow changes, without additional phlebotomy. Nearly 1 in 11 screened neonates tested positive for G6PD deficiency.

Heinz bodies occur in patients experiencing specific drug-induced acute haemolytic crises, most often in those with an inherited deficiency in glucose-6-phosphate dehydrogenase activity. Laboratory methods for quantifying Heinz bodies in in vitro systems include direct microscopic counts from crystal violet-stained thin blood films or spectrophotometric measurement of free crystal violet in RBC suspensions treated for Heinz body induction. Each method is relatively laborious and prone to errors. In this study, we sought to evaluate and validate an improved flow cytometry-based method for detecting Heinz bodies in human red blood cells after in vitro exposure to phenylhydrazine using washed RBCs. We report good concordance between flow cytometric counts of Heinz bodies and microscopic and spectrophotometric analyses of the same suspensions. Flow cytometry offers a less laborious, more precise, and more accurate quantification of Heinz body formation, with strong potential to improve the ease of use in experimental applications.

Genomic sequencing has the potential to transform newborn screening (NBS) for rare diseases but raises significant pragmatic, clinical, psychosocial, ethical, and policy issues. Evidence is urgently needed to guide policy as healthcare systems around the world contemplate implementation. In 2025, four major genomic NBS (gNBS) studies, totaling over 10,800 newborns from the US, Belgium, and Australia, published initial results. The adoption of different approaches to key implementation issues in diverse healthcare systems by these studies allows us to draw comparisons and enable collective learning. All studies reported successful use of dried blood spots for DNA extraction, which supports integration with existing NBS infrastructure. Experience with automation of genomic data analysis and reporting was variable, with valuable insights gained about balancing sensitivity, specificity, scalability, and resource utilization going forward. The screen-positive rate ranged from 1.6% to 3.7%, with G6PD deficiency by far the most common condition identified. Further comparison of results was limited by wide variation in the number and type of conditions included and by inconsistencies in how outcomes were defined and reported, highlighting the need for greater harmonization of study designs and data collection. The ability to deliver gNBS at the scale and pace that would be required for a public screening program remains untested, and data on long-term outcomes and costs are still needed. Concerns also remain about inequitable access and outcomes, particularly for families at socioeconomic, linguistic, and geographical disadvantage, and these key questions need to be addressed next as the field continues to evolve.